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Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer : multi-centre phase I/II study
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Loriot, Yohann, Fizazi, Karim, Jones, Robert J., Van den Brande, Jan, Molife, Rhoda L., Omlin, Aurelius, James, Nicholas D., Baskin-Bey, Edwina, Heeringa, Marten, Baron, Benoit, Holtkamp, Gertjan M., Ouatas, Taoufik and De Bono, Johann S. (2014) Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer : multi-centre phase I/II study. Investigational New Drugs, 32 (5). pp. 995-1004. doi:10.1007/s10637-014-0101-x ISSN 0167-6997.
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Official URL: http://dx.doi.org/10.1007/s10637-014-0101-x
Abstract
BACKGROUND:
ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumour activity in in vitro and in vivo preclinical models.
MATERIAL AND METHODS:
This first-in-man phase I/II study utilised a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed.
RESULTS:
Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part.
CONCLUSIONS:
In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity.
Item Type: | Journal Article | ||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Cancer Research Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Journal or Publication Title: | Investigational New Drugs | ||||||
Publisher: | Springer New York LLC | ||||||
ISSN: | 0167-6997 | ||||||
Official Date: | October 2014 | ||||||
Dates: |
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Volume: | 32 | ||||||
Number: | 5 | ||||||
Page Range: | pp. 995-1004 | ||||||
DOI: | 10.1007/s10637-014-0101-x | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Restricted or Subscription Access |
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